The central hypothesis to be tested in this proposal is that diabetes-associated endothelial dysfunction is mediated in part by the interaction of modified HDL, CD36 and caveolin-2 which results in the inhibition of endothelial nitric oxide synthase. One of the most prevalent and deadly complications of diabetes is cardiovascular disease. The recent "Atherosclerosis Risk in Communities Study" reported that the development of type II diabetes was nearly 2.5 times more likely in patients with hypertension than in normotensive patients. In addition, the UK Prospective Diabetes Study and the Heart Outcomes Prevention Evaluation have demonstrated that lowering blood pressure in diabetic patients greatly lessens the risk of several cardiovascular diseases. Endothelial dysfunction is centrally involved in many of the complications caused by diabetes, including hypertension. One of the mechanisms by which endothelial cells influence blood pressure is by the generation of nitric oxide. Previous studies have demonstrated that the ability of endothelial cells to generate nitric oxide is compromised when exposed either in vitro or in vivo to a diabetic environment. The mechanisms by which diabetes can inhibit nitric oxide generation and thus decrease the vasodilation of a vessel are not well understood. One intriguing possibility is that the diabetic serum may be acting through a cell surface receptor such as CD36. In addition, preliminary data demonstrate that HDL isolated from the serum of diabetic humans or mice will inhibit the generation of nitric oxide in a CD36 and caveolin-2 dependent manner. The goal of the proposed studies is to determine the mechanism(s) whereby the interaction of diabetic HDL, CD36 and caveolin-2 results in the inhibition of endothelial nitric oxide synthase. Aim 1: To determine the domain(s) within CD36 and caveolin-2 that permits the two proteins to associate and subsequently inhibit endothelial nitric oxide synthase. Aim 2: To determine the role of phosphorylation and acylation of caveolin-2 in the inhibition of endothelial nitric oxide synthase. Aim 3: To determine the mechanism(s) whereby diabetic HDL/CD36/caveolin-2 interaction inhibits endothelial nitric oxide synthase. Aim 4: To determine if the removal of CD36 or caveolin-2 from leprdb null mice (a mouse model of type II diabetes) protects endothelial nitric oxide synthase activity and vascular responsiveness to agonists that stimulates nitric oxide generation.